Fetomaternal hemorrhage in monochorionic diamniotic twins at 37+ weeks’ gestation: A rare complication

Introduction

Monochorionic diamniotic (MCDA) twin pregnancy results from the division of a single fertilized egg between the 4th and 8th days after fertilization and accounts for approximately 30% of monozygotic twin pregnancies. The characteristic of this type of twin pregnancy is that the two fetuses share a single placenta but have separate amniotic sacs. Studies have shown that the incidence of perinatal maternal and fetal complications in MCDA twin pregnancy is significantly higher than that in dichorionic diamniotic (DCDA) twin pregnancy.^1,2 Due to shared placental circulation, MCDA twins are prone to a variety of serious complications, including twin-to-twin transfusion syndrome (TTTS), selective fetal growth restriction (sFGR), twin anemia–polycythemia sequence, and the rarely reported fetomaternal hemorrhage (FMH).^3–7

FMH refers to a clinical syndrome in which a certain amount of fetal blood enters the maternal circulation through the placental villous spaces under the action of specific inducing factors, thereby causing fetal anemia or a maternal hemolytic reaction. ⁸ The disease can occur at any stage of pregnancy or during delivery. ⁹ In 1954, Chown first reported a case of FMH, and since then, research on FMH has gradually increased. Existing data have shown that the incidence of FMH in singleton pregnancies is 0.02%–0.3%. ⁵ In MCDA twin pregnancies, the risk of FMH may further increase because of the unique placental vascular structure. FMH is characterized by concealed clinical manifestations and a lack of specificity, leading to considerable difficulty in clinical diagnosis. Given that the onset of FMH is insidious and may cause serious adverse pregnancy outcomes, early recognition and intervention play a key role in improving the prognosis of perinatal infants. ¹⁰ This paper reports a case of sudden FMH in an MCDA twin pregnancy, reviews the relevant literature on MCDA twin pregnancies complicated by severe FMH, and systematically summarizes the current research status of this rare disease.

Case presentation

A 39-year-old woman with monochorionic diamniotic (MCDA) twins presented at 37 + 3 weeks’ gestation for abnormal fetal heart rate monitoring. There was no history of invasive procedures during pregnancy, and no other abnormalities were detected on prenatal examination. Prior to admission, fetal heart rate monitoring at 36 + 3 weeks of gestation indicated that both fetuses were reactive. Fetal ultrasound at 36 + 3 weeks of gestation shows a twin pregnancy in utero with ongoing fetal survival. Fetus A was in breech presentation, with measurements of BPD 85 mm, HC 308 mm, AC 302 mm, FL 64 mm, and AFV 51mm. MCA Doppler showed PI 1.22, RI 0.68, S/D 3.1, Vm 25 cm/s, and PSV 45 cm/s. Fetus B was in cephalic presentation, with measurements of BPD 84 mm, HC 307 mm, AC 281 mm, FL 64 mm, and AFV 51 mm. MCA Doppler showed PI 1.24, RI 0.71, S/D 3.4, Vm 29 cm/s, and PSV 52 cm/s. MCA-PSV values were within the expected range for the gestational age. Given the MCDA pregnancy at 36 + 3 weeks with unilateral fetal growth restriction (FGR) in fetus B, a time-constrained plan for delivery was recommended. The pregnant woman delayed returning to the hospital until 37 + 3 weeks of gestation. At admission, the pregnant woman had no symptoms, such as reduced fetal movement, and sinusoidal fetal heart rate patterns were observed in both fetuses (Figure 1(a)). An emergency cesarean delivery was performed because of fetal distress, with a decision-to-delivery interval of 27 min. No vascular anastomoses were found in the placenta during the operation. Both neonates were delivered with severe neonatal asphyxia and anemia but achieved favorable recovery after resuscitation and transfusion support. Postoperative hemoglobin F (HbF) in maternal blood was markedly elevated at 11.93%, confirming significant fetomaternal hemorrhage (FMH). Pathologic examination of the placentae and umbilical cords showed aging changes consistent with late gestation, and no placental tumor was identified. We found increased nucleated red blood cells in the placentas (Figure 1(b)). Immunohistochemical staining demonstrated vascular endothelial growth factor (VEGF), CD34, and CD31 expression in the capillary endothelial cells (Figure 1(c) to (e)). The patient was discharged on postoperative day 5. Newborn A was male, with a birth weight of 2300 g. The Apgar score at birth was 1/-/-, and endotracheal intubation was performed because of severe neonatal asphyxia. Umbilical cord blood gas analysis showed pH 6.742, pO2 148 mmHgpCO2 40 mmHg, base excess −22.5 mmol/L, and lactate 18 mmol/L. Laboratory examination showed WBC 31.27 × 10⁹/L, Hb 28 g/L, and platelets 42 × 10⁹/L. Management included respiratory support, mild hypothermia therapy, peritoneal dialysis, plasma and platelet transfusions, antibiotics, nutritional support, and supportive care. The infant was discharged from the neonatal intensive care unit (NICU) on day 29, with normal development reported at follow-up. Newborn B was male, with a birth weight of 2015 g. The Apgar scores were 2/5/7, and the infant was transferred to the NICU because of severe neonatal asphyxia and severe anemia. Laboratory examination showed WBC 24.95 × 10⁹/L, Hb 29 g/L, and platelets 151 × 10⁹/L. Management included respiratory support, mild hypothermia therapy, peritoneal dialysis, transfusions, and supportive care. The infant was discharged from the NICU on day 24, with normal development reported at follow-up. Both newborns recovered without reported long-term neurodevelopmental sequelae during follow-up.

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Figure 1.

Fetal heart rate monitoring and placental immunohistochemistry in our MCDA cases vs. uncomplicated MCDA twin pregnancies. (a) to (e) Our case: (a) Cardiotocography showing sinusoidal fetal heart rate patterns in both fetuses. (b) H&E sections showing mildly increased nucleated red blood cells (arrows) within placental vessels and intervillous spaces. (c) to (e) VEGF, CD31, and CD34 immunohistochemical staining of placental tissues from the FMH case. (f) to (i) Uncomplicated MCDA twin placentas: (f) H&E section. (g) to (i) VEGF, CD31, and CD34 immunohistochemical staining. Images in (b) to (i) were acquired at an original magnification of 100×.

Discussion

Under normal conditions, maternal and fetal circulations are separated by the placental barrier formed by the syncytiotrophoblast and cytotrophoblast layers, which prevents the direct exchange of red blood cells. ¹¹ Nevertheless, trace fetomaternal transfusion can occur, and a very small amount of fetal red blood cells (RBCs) may enter the maternal circulation as a physiologic phenomenon during pregnancy.^7,12 Only when blood loss reaches a significant volume, such as 20% of the fetoplacental blood volume, or occurs rapidly can it become symptomatic.^13,14 Pathogenetically, FMH involves a pressure gradient between the umbilical artery and the intervillous space, allowing fetal blood to enter the maternal circulation either slowly or rapidly. This transfer can occur during prenatal procedures (e.g. amniocentesis), in the presence of placental lesions such as chorioangioma, or during strong uterine contractions during labor. ¹² Most FMH events have no clearly identifiable etiology and are considered idiopathic. Reported high-risk factors include fetal abnormalities (e.g. edema, twin-to-twin transfusion, monochorionic pregnancies, intrauterine growth restriction), placental pathologies (e.g. placental abruption, placental tumors, implantation abnormalities, placenta previa, chorioangioma, choriocarcinoma, umbilical vein thrombosis, single umbilical artery), and maternal factors (hypertension, trauma, substance abuse such as cocaine use, obstetric interventions, etc.).^15–18

Several etiologies and predisposing factors for FMH may explain its underlying pathogenetic mechanisms. Placental barrier disruption is considered the most common pathological change in FMH. Fetomaternal hemorrhage (FMH) is a rare complication of external cephalic version (ECV). Scholz et al. ¹⁹ reported that ECV at term is a safe procedure that reduces the incidence of cesarean delivery for breech presentation. However, one recognized complication is ECV-related disruption of the placental barrier, which may result in the transfer of fetal blood into the maternal circulation. Ghidini and Korker ²⁰ found that FMH after ECV is uncommon. A review of studies using the Kleihauer–Betke test showed a prevalence of 2.4% (95% CI: 1.4%–3.9%). Lemaitre et al. ²¹ reported a low rate of FMH (1.8%) after attempted ECV, with no adverse fetal or neonatal outcomes observed in cases with a positive Kleihauer–Betke test, even when a large volume (>5 mL) of fetal blood was detected. Manual ECV involves manipulation and rotation of the fetus, which may stretch or twist the placenta or damage the placental villous blood vessels. Such disruption compromises the placental barrier that normally separates maternal and fetal blood, thereby allowing fetal blood to enter the maternal circulation. Choriocarcinoma is another condition associated with FMH, and its pathogenesis has been relatively well studied. Hui noted that gestational choriocarcinoma is the most common form of gestational trophoblastic neoplasia. It is characterized by aggressive, destructive growth and a marked tendency for hematogenous dissemination, leading to high mortality if untreated. ²² Stabile et al. ²³ demonstrated that choriocarcinoma is predominantly driven by infiltration of the uterine wall and maternal vascular spaces, directly precipitating FMH. The same authors also reported that fetal anemia arising from benign placental lesions—such as chorangiomatosis and multiple chorangioma syndrome—is typically attributed to blood sequestration within the lesion itself. Collectively, these findings suggest that placental pathology, whether malignant or benign, can serve as a critical initiating factor in FMH, highlighting the central role of placental abnormalities in the pathogenesis of this condition. Stefanovic noted that the diagnosis of massive FMH should be considered in all cases of unexplained fetal death, severe fetal distress of unknown etiology, nonimmune fetal hydrops, and nonhemolytic neonatal anemia. In all cases of massive FMH, it is essential to submit the placenta for examination by an experienced pathologist and to perform serial human chorionic gonadotropin monitoring after delivery to exclude choriocarcinoma. ²⁴ Nevertheless, the etiology and pathogenesis remain unclear in many cases.

Multiple characteristic placental histopathological abnormalities and altered angiogenic biomarkers are closely associated with the occurrence of spontaneous massive fetomaternal hemorrhage (FMH). Intervillous thrombi, increased nucleated RBCs, syncytial knots, parenchymal pallor, and placental villous edema have also been associated with FMH. Herein, we describe two cases of spontaneous massive fetomaternal hemorrhage. Hematoxylin and eosin (H&E) slides were reviewed to identify relevant lesions, and paraffin blocks were stained with endothelial markers (VEGF, CD34, and CD31) with emphasis on angiogenesis. VEGF is a major mediator of endothelial cell angiogenesis that influences the degree of villous vascularization and terminal villus formation. CD34 is widely used as a marker of vascular endothelial progenitor cells. CD31 is a pan-endothelial marker expressed in blood and lymphatic vessels. These markers play important roles in angiogenesis. ²⁵ Immediate postpartum assessment of the placenta in our case revealed no obvious vascular anastomoses on visual inspection. Given the critical priority of ensuring neonatal survival in this emergency setting, the optimal window for specialized investigations, such as placental vascular perfusion, was missed. Additionally, because of our hospital’s current technical limitations, further verification by vascular casting could not be performed.

The most common clinical manifestation of FMH is reduced or absent fetal movement. ²⁶ A search of multiple domestic and international databases identified three reports of FMH in monochorionic diamniotic (MCDA) pregnancies.^5–7 Watanabe et al. ⁶ and Yoo et al. ⁷ found that FMH in MCDA twin pregnancies showed reduced fetal activity. However, twin pregnancies have unique characteristics, including the possibility of reduced or even absent movement in one fetus. Therefore, pregnant women may not perceive reduced fetal movement, and the clinical presentation may be atypical. Abnormal fetal heart rate patterns are important adjunctive tools for the early diagnosis of FMH. The literature indicates that a sinusoidal fetal heart rate pattern is strongly associated with fetal anemia and related conditions, although its diagnostic performance is limited. In a systematic review of fetal anemia, the sinusoidal pattern had very low sensitivity (approximately 3%), with only one of 32 anemic fetuses demonstrating a sinusoidal trace during pregnancy. However, among cases with sinusoidal patterns, 48 of 232 (approximately 20.7%) were ultimately diagnosed with fetal anemia, indicating higher but still imperfect specificity.^{6,14,18,27–71} Among the 48 cases with both a sinusoidal fetal heart rate pattern and fetal anemia, only one case involved ABO hemolysis, one involved TTTS, and the remaining 46 were attributable to FMH. These findings suggest that FMH is the predominant cause of sinusoidal fetal heart rate patterns in the setting of fetal anemia, with important implications for rapid clinical recognition and timely intervention. This case had a sinusoidal pattern of fetal heart rate monitoring at the time of FMH, which is consistent with the report of Watanabe et al., ⁶ with a mechanism related to fetal autonomic nervous system dysregulation secondary to severe anemia. ⁷² Other abnormalities include reduced or absent baseline variability, repetitive decelerations, bradycardia, and signs of fetal distress. ²⁶

Obstetric ultrasound is a crucial auxiliary examination. Severe fetal anemia may present as fetal edema or stillbirth on ultrasound. When the peak systolic velocity of the fetal middle cerebral artery (MCA-PSV) is ≥1.5MoM, it is highly suggestive of fetal anemia.^5,12,71 However, this does not imply that all anemic fetuses will exhibit an increased middle cerebral artery peak systolic velocity. ⁷³ Laboratory methods commonly used to detect FMH include the Kleihauer–Betke (KB) test and flow cytometry.^41,74–78 Both approaches rely on identifying fetal HbF in the maternal circulation and indirectly assess fetal blood loss by quantifying the proportion of fetal RBCs in maternal blood samples. In the three reported MCDA twin pregnancies, fetal HbF ranged from 1.9% to 6.6%. In the present case, the HbF level measured by flow cytometry was 11.93%, indicating more severe FMH than in the previously reported cases.^5–7 Additionally, the literature indicates that maternal serum alpha-fetoprotein (AFP) levels may be elevated in FMH.^5,79 Umbilical artery blood gas analysis has also been proposed as a rapid diagnostic modality for FMH. ⁸⁰ Emerging diagnostic approaches include immunosensors for FMH detection. ⁸¹

Timely termination of pregnancy is an important strategy to improve the prognosis for mothers and infants affected by FMH. Regarding the timing of termination in twin pregnancies, the 10th edition of Obstetrics and Gynecology recommends delivery at 35–37 weeks for twin pregnancies with a single chorion and diamniotic. The 2023 guidelines from the Society of Obstetricians and Gynaecologists of Canada clearly recommend terminating uncomplicated monochorionic diamniotic twin pregnancies at 36–37 weeks, avoiding delivery after 37 weeks. ⁸² China's Guidelines for Clinical Management of Twin Pregnancy also endorse 37 weeks as a safe threshold for delivery. The common principle across these recommendations is to balance neonatal survival with the risks associated with prolonged pregnancy. In MCDA twin pregnancies, declining placental function and hemodynamic instability after 37 weeks are associated with increased perinatal mortality. In the present case, the obstetrician recognized the MCDA twin pregnancy complicated by unilateral FGR and strongly recommended hospitalization for delivery. The patient elected cesarean delivery but requested to return home to determine the delivery date. The sudden onset of FMH at 37 + 3 weeks provides additional clinical support for using 37 weeks as a safe threshold for delivery in this setting. Immediate neonatal resuscitation and management of complications, including anemia (with transfusion as needed), potential hyperbilirubinemia, and supportive care, are essential after birth. Prompt transfusion and, when indicated, exchange transfusion are critical for improving prognosis. For FMH with low fetal blood volume, simple transfusion is preferred; for cases without low blood volume, exchange transfusion may be indicated. ⁸³ Given that up to 40% of severe FMH cases may be missed, clinicians should consider FMH in the differential diagnosis of unexplained fetal anemia or pallor at birth and perform appropriate diagnostic testing. ⁸⁴ In neonates with severe anemia, timely transfusion is crucial.^85,86

Perinatal prognosis depends on the acuity and severity of FMH and the extent of fetal blood loss. When gestational age is less than 32 weeks, particularly in the presence of severe fetal anemia (e.g. fetal edema), intrauterine red blood cell transfusion can rapidly correct fetal anemia, and the associated complication and mortality rates may be lower than those associated with early delivery. ⁸⁷ Although severe anemia requiring intrauterine transfusion is rare in MCDA twin pregnancies with a double amniotic sac, the reported cases have demonstrated favorable therapeutic outcomes.^88,89 Intrauterine blood transfusion remains a highly effective intervention for the treatment of fetal anemia. ⁹⁰ For pregnancies at or beyond 32 weeks of gestation, fetal-maternal transfusion syndrome may recur, and the risks associated with intrauterine transfusion during treatment or recurrent FMH may exceed the obstetric risks of prematurity. If the fetomaternal transfusion volume is ≥20% of the fetal blood volume, or if the fetal middle cerebral artery peak systolic velocity (MCA-PSV) is ≥1.5 MoM, immediate cesarean delivery is recommended, with preparation for rapid neonatal transfusion after birth.^7,28 Although severe anemia may be present at birth, with timely and effective resuscitation, the prognosis for most newborns is favorable, and neurodevelopmental outcomes are generally comparable to those of unaffected infants.^91,92 In this case, the pregnancy was terminated in a timely manner and the neonates were transferred to the NICU for follow-up care. At present, both newborns were in good condition.

Conclusion

MCDA twin pregnancies pose unique risks because of shared placental circulation. FMH, although rare, can present suddenly at term with severe fetal anemia and fetal distress. Prompt recognition, rapid delivery when indicated, and aggressive neonatal resuscitation and transfusion can lead to favorable maternal and neonatal outcomes. This case underscores the importance of maintaining a high index of suspicion for FMH in MCDA pregnancies and aligning the timing of delivery with the acute clinical presentation to optimize prognosis. Although early detection and timely rescue can improve the prognosis of mothers and infants, MCDA twin pregnancies must terminate pregnancy before 37 weeks according to the guidelines, otherwise unpredictable complications, including sudden severe FMH, may occur.